Mitochondrial Dysfunction and Apoptosis Are Attenuated on κ-Opioid Receptor Activation Through AMPK/GSK-3β Pathway...

Area of Science:

• Cardiology
• Pharmacology
• Molecular Biology

Background:

• Kappa-opioid receptor (KOR) activation demonstrates cardioprotective effects against myocardial ischemia and reperfusion (MI/R) injury.
• Mitochondrial dysfunction is a key factor in MI/R injury, but its regulation by KOR remains unclear.

Purpose of the Study:

• To investigate KOR's role in regulating mitochondrial dysfunction post-MI/R.
• To elucidate the underlying molecular mechanisms, focusing on the AMPK/GSK3β pathway.

Main Methods:

• Established in vivo MI/R rat models and in vitro hypoxia/reoxygenation cardiomyocyte models.
• Assessed mitochondrial morphology and function, and cardiomyocyte apoptosis.
• Utilized selective KOR agonist (U50,488H), antagonist (nor-BNI), AMPK inhibitor (Compound C), and GSK3β inhibitor (AR-A014418).
• Investigated protein expression and phosphorylation of AMPK and GSK3β, including siRNA knockdown of AMPKα.

Main Results:

• U50,488H treatment reduced apoptosis and improved mitochondrial morphology and function in MI/R models.
• These protective effects were abrogated by KOR antagonist, AMPK inhibitor, and GSK3β inhibitor.
• U50,488H increased phosphorylation of AMPK and GSK3β in cardiomyocytes.
• AMPK activation led to GSK3β phosphorylation, while AMPKα siRNA reduced both phosphorylations.

Conclusions:

• Kappa-opioid receptor activation confers cardioprotection against MI/R injury.
• This protection is mediated by improved mitochondrial morphology and function via the KOR-AMPK/GSK3β signaling pathway.